Project Summary Eye injuries are one of the major causes of blindness worldwide, and in the United States alone 2.5 million eye injuries occur every year. Ocular surface injuries disrupt corneal angiogenic privilege and trigger corneal neovascularization (CNV), eventually leading to loss of vision. Ocular drug delivery, although it may seem to be deceptively simple, is a challenging task mainly because of the unique barriers associated with the ocular surface that impede adequate drug delivery and therapeutic efficacy. Topical drug therapy with eye drop formulations is the most accessible and noninvasive. However, its potential is limited by the ocular surface protective barriers, such as reflex tearing, constant blinking, impervious nature of the ocular surface due to epithelial tight junctions, and nasolacrimal drainage that can rapidly clear the eye drops from the ocular surface within a few minutes. These physiological barriers contribute to inadequate drug delivery and reduced bioavailability of the drug to the eye. Hence, topical eye drops must be applied several times a day, thus increasing the potential for toxic side effects such as cellular damage, inflammation of the ocular surface, and temporary blurred vision, leading to discomfort and poor patient compliance. This research endeavor focuses on the development of an ocular drug delivery nanowafer with controlled drug release attributes. The nanowafer can be simply applied on the cornea with a fingertip, like a contact lens. The nanowafer can deliver the drug in a controlled release fashion for several weeks, thus increasing the drug residence time on the ocular surface, improving therapeutic efficacy, and treatment compliance. The nanowafer will be fabricated using mucoadhesive polymers, so that it can readily adhere to the ocular surface and withstand constant blinking. The nanowafer is highly transparent and will have negligible effect on normal vision. During the course of the drug release, the nanowafer slowly dissolves and fades away, i.e., self-clearing. The three specific aims of this project are: (1) Nanowafer fabrication and optimization of total drug content and drug stability; (2) Optimization of in vivo pharmacokinetics and maximum tolerated drug dose; and (3) Evaluation of nanowafer efficacy on inhibition of corneal neovascularization. Successful completion of this research endeavor will result in an ocular drug delivery nanowafer that can release the drug for several weeks. The nanowafer can enhance the therapeutic efficacy, minimize drug related side effects and improve patient compliance. Since, the polymers and drugs used in the nanowafer fabrication are already in clinical use, the nanowafer can be rapidly translated to the clinic for treating CNV. Furthermore, the nanowafer drug delivery system developed for treating CNV can find potential applications in treating other eye diseases, such as sight-threatening injuries, corneal inflammation, ocular surface infections, dry eye, corneal cystinosis, and glaucoma.